Solution Chemistry of Copper(II) Binding to Substituted 8-Hydroxyquinolines

Abstract

8-Hydroxyquinolines (8HQs) are a family of lipophilic metal ion chelators that have been used in a range of analytical and pharmaceutical applications over the last 100 years. More recently, CQ (clioquinol; 5-chloro-7-iodo-8-hydroxyquinoline) and PBT2 (5,7-dichloro-2-[(dimethylamino)methyl]-8-hydroxyquinoline) have undergone clinical trials for the treatment of Alzheimer's disease and Huntington's disease. Because CQ and PBT2 appear to redistribute metals into cells, these compounds have been redefined as copper and zinc ionophores. Despite the attention surrounding the clinical trials and the clear link between 8HQs and metals, the fundamental solution chemistry of how these compounds bind divalent metals such as copper and zinc, as well as their mechanism(s) of action in mammalian systems, remains poorly understood. In this study, we used a combination of X-ray absorption spectroscopy (XAS), high-energy resolution fluorescence detected (HERFD) XAS, electron paramagnetic resonance (EPR), and UV−visible absorption spectroscopies to investigate the aqueous solution chemistry of a range of 8HQ derivatives. To circumvent the known solubility issues with 8HQ compounds and their complexes with Cu(II), and to avoid the use of abiological organic solvents, we have devised a surfactant buffer system to investigate these Cu(II) complexes in aqueous solution. Our study comprises the first comprehensive investigation of the Cu(II) complexes formed with many 8HQs of interest in aqueous solution, and it provides the first structural information on some of these complexes. We find that halogen substitutions in 8HQ derivatives appear to have little effect on the Cu(II) coordination environment; 5,7-dihalogenated 8HQ conformers all have a pseudo square planar Cu(II) bound by two quinolin-8-olate anions, in agreement with previous studies. Conversely, substituents in the 2-position of the 8HQ moiety appear to cause significant distortions from the typical square-planar-like coordination of most Cu(II)-bis-8HQ complexes, such that the 8HQ moieties in the Cu(II)-bis-8HQ complex are rotated approximately 30−40°apart in a "propeller-like" arrangement.

Copper(II) Binding to PBT2 Differs from That of Other 8-Hydroxyquinoline Chelators: Implications for the Treatment of Neurodegenerative Protein Misfolding Diseases

“…EPR spectra were simulated to generate the g and A values listed in Table , and the simulated spectra are shown in Figure a and b. The spectra of Cu­(II)- bis -PBT2 were best simulated by rhombic g values (where g x ≠ g y ≠ g z ), similar to EPR spectra of Cu­(II)- bis -8HQ and -M8Q described previously but in contrast to previous EPR investigations of Cu­(II) 8HQ complexes which assumed axial symmetry. An anisotropic rhombic g tensor with g x ≠ g y is expected because these complexes do not possess true axial symmetry even in the coplanar Cu­(II)- bis -8HQ complexes.…”

“…The five-line pattern in the A region of the second derivative is consistent with two approximately equivalent nitrogens bound to the Cu­(II) with a coupling of 20.2 MHz and was not fit well without including nitrogen hyperfine structure in the fit parameters. Previously, spectra of the coplanar Cu­(II)- bis -8HQ and the distorted 2-CH 3 -substituted Cu­(II)- bis -M8Q complex showed prominent nitrogen hyperfine structure from approximately equivalent nitrogen ligands with hyperfine coupling values of 15.3 and 14.0 MHz, respectively . In spectra of Cu­(II)- bis -PBT2, nitrogen hyperfine splitting is visible only in the second derivative and has a larger coupling.…”

“…8-Hydroxy­quinoline compounds, and particularly their Cu­(II) complexes, are hydrophobic, resulting in a number of solubility issues, namely, precipitate formation, in many previous studies on PBT2 , and other 8HQs. ,− As a result of this low solubility, nearly all experimental work reported to date on such complexes has used powders, crystals, or abiological solvents such as dimethyl sulfoxide (DMSO), di­methyl­formamide (DMF), or toluene. We previously devised a buffer system that includes a surfactant (dodecyl tri­methyl­ammonium bromide (DTAB) in 3-( N -morpholino)­propane­sulfonic acid (MOPS)) to allow us to probe Cu­(II) 8HQ complexes in aqueous solution at physiological pH . Our buffered surfactant solution is closer to a true aqueous solution, which is the goal in studying systems with biological applications.…”

“…We have previously investigated the solution structures of Cu­(II) complexes with other 8-hydroxyquinolines (8HQs) using X-ray absorption spectroscopy (XAS) and high-energy-resolution fluorescence-detected X-ray absorption spectroscopy (HERFD) XAS. , Structures of other Cu­(II) complexes with 8HQ-based ligands have also been investigated previously by other groups. − The chemical identity of PBT2 was released in 2014 (patented by Prana Biotechnology Ltd.); structural studies have therefore been limited until relatively recently. However, Kenche et al investigated the solution structure of a similar 8HQ compound without chlorine substituents, 2-[(di­methyl­amino)­methyl]-8-hydroxy­quinoline, using electron paramagnetic resonance (EPR) and UV–visible absorption spectroscopy along with geometry optimization calculations to propose two possible structures for this ligand, dependent on solution conditions.…”

“…To better understand the aqueous solution chemistry of PBT2, we investigated the structure of Cu­(II) complexes with PBT2 using a combination of conventional spectroscopies, including EPR and UV–visible absorption, as well as synchrotron XAS and HERFD XAS. To circumvent the known solubility issues with 8-hydroxyquinoline compounds and their complexes with Cu­(II) and to avoid the use of organic solvents, we have again used a buffer system that includes a surfactant to allow us to probe the Cu­(II) PBT2 complex­(es) in aqueous solution at physiological pH . We show that PBT2 binds Cu­(II) in a different coordination environment from that of other 8HQs in solution .…”